key: cord-0295319-kuhw6gfw
authors: Yang, L. M.; Costales, C.; Ramanathan, M.; Bulterys, P. L.; Murugesan, K.; Schroers-Martin, J.; Alizadeh, A. A.; Boyd, S. D.; Brown, J. M.; Nadeau, K. C.; Nadimpalli, S. S.; Wang, A. X.; Busque, S.; Pinsky, B. A.; Banaei, N.
title: Cell-mediated and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients
date: 2022-01-05
journal: nan
DOI: 10.1101/2022.01.04.22268750
sha: 9940af8706869eb218aadd0a13c5f1af1e517e31
doc_id: 295319
cord_uid: kuhw6gfw

Importance: Data on the humoral and cellular immune response to primary and booster SARS-CoV-2 vaccination in immunosuppressed patients is limited. Objective: To determine humoral and cellular response to primary and booster vaccination in immunosuppressed patients and identify variables associated with poor response. Design: Retrospective observational cohort study. Setting: Large healthcare system in Northern California. Participants: This study included patients fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) who underwent clinical testing for anti-SARS-SoV-2 S1 IgG ELISA (anti-S1 IgG) and SARS-CoV-2 interferon gamma release assay (IGRA) from January 1, 2021 through November 15, 2021. A cohort of 18 immunocompetent volunteer healthcare workers were included as reference. No participants had a prior diagnosis of SARS-CoV-2 infection. Exposure(s): Immunosuppressive diseases and therapies. Main Outcome(s) and Measure(s): Humoral and cellular SARS-CoV-2 vaccine response as measured by anti-S1 IgG and SARS-CoV-2 IGRA, respectively, after primary and booster vaccination. Results: 496 patients (54% female; median age 50 years) were included in this study. Among immunosuppressed patients after primary vaccination, 62% (261/419) had positive anti-S1 IgG and 71% (277/389) had positive IGRA. After booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Immunosuppressive factors associated with low rates of humoral response after primary vaccination included anti-CD20 monoclonal antibodies (n=48, P<.001), sphingosine 1-phsophate (S1P) receptor modulators (n=11, P<.001), mycophenolate (n=78, P=.002), and B cell lymphoma (n=55, P=.004); those associated with low rates of cellular response included S1P receptor modulators (n=11, P<.001) and mycophenolate (n=69, P<.001). Of patients who responded poorly to primary vaccination, 16% (4/25) with hematologic malignancy or primary immunodeficiency developed a significantly increased humoral response after the booster dose, while 52% (14/27) with solid malignancy, solid organ transplantation, or autoimmune disease developed an increased response (P=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose. Conclusions and Relevance: Cellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies.

3 vaccination included anti-CD20 monoclonal antibodies (P<.001), sphingosine 1-phsophate (S1P) receptor modulators (P<.001), mycophenolate (P=.002), and B cell lymphoma (P=.004); those associated with low rates of cellular response included S1P receptor modulators (P<.001) and mycophenolate (P<.001). Of patients who responded poorly to primary vaccination, 16% (4/25) with hematologic malignancy or primary immunodeficiency developed a significantly increased humoral response after the booster dose, while 52% (14/27) with solid malignancy, solid organ transplantation, or autoimmune disease developed an increased response (P=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose.

Conclusions and Relevance: Cellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies. All rights reserved. No reuse allowed without permission.

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One of every 25 individuals in the U.S. is estimated to be immunocompromised 1 and potentially at increased risk for severe COVID-19 2 and breakthrough infections after vaccination 3 . Studies have demonstrated poor humoral response to SARS-CoV-2 vaccination in immunosuppressed patients 4, 5 . On the other hand, cellular, or T cell vaccine responses appear to be less impaired in certain immunosuppressed groups, but are less well characterized [6] [7] [8] . Due to the decline in antibody titers over time after vaccination, booster shots have been recommended for all adults 9, 10 . Boosters are thought to be especially important for immunosuppressed patients due to their impaired response to primary vaccination [11] [12] [13] . Here, we compare the humoral and cellular immune responses to SARS-CoV-2 after primary and booster vaccination among immunosuppressed patients. By retrospective analysis, we identify immunosuppressive factors that contribute to impaired response.

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This study was approved by the Stanford University Institutional Review Board (IRB-60171 and IRB-57519). Informed consent was obtained from volunteer healthcare workers before blood collection.

Assay design and interpretation for the anti-SARS-CoV-2 S1 IgG (anti-S1 IgG) assay, ACE2 blocking activity assay, and SARS-CoV-2 interferon gamma (IFN-γ) release assay (IGRA) are described in eMethods. We retrospectively assessed patients with IGRA ordered as part of clinical testing for patients at Stanford Health Care from January 1, 2021 through November 15, 2021. We also recorded available anti-S1 IgG antibody results. We performed two main analyses: primary vaccination response and booster response. Those patients with anti-S1 IgG or IGRA results collected at least 14 days following receipt of the second dose of either the Moderna mRNA-1273 or the Pfizer/BioNTech BNT162b2 mRNA vaccines or single dose of the Janssen Ad26.COV2.S vaccine were included in the primary vaccination analysis. One additional dose with any of the three vaccines was considered a booster dose. Patients with anti-S1 IgG or IGRA collected at least seven days following receipt of a booster dose were included in the booster analysis.

Electronic medical record (EMR) review was performed by one of five physician authors (NB, PB, CC, MR, LY) to collect data on underlying disease and active immune-suppressive/modulatory therapy (ISMT), including chemical drugs, biologics, and cellular therapy, such as hematopoietic stem cell transplant (HSCT) and CAR-T. Active ISMT was defined by the following conditions: receiving therapy 1) at the time of, or 2) up to four weeks prior (up to one year prior for HSCT and CAR-T) to administration of the first SARS-CoV-2 vaccine dose, or 3) anytime between administration of the first vaccine dose and the time of anti-S1 IgG and IGRA testing. ISMTs were additionally categorized by mechanism of action (eTables 1,2). All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted January 5, 2022. ; https://doi.org/10.1101/2022.01.04.22268750 doi: medRxiv preprint Immunosuppressive conditions were subcategorized by disease mechanism (eTables 3,4) and stratified into the following categories: hematologic malignancy with active disease at the time of initial vaccination or anytime between vaccination and testing (active heme malignancy), hematologic malignancy with complete response to therapy as per imaging or pathologic diagnosis (inactive heme malignancy), primary hematologic disease of anemia (primary anemia), solid non-hematologic malignancy with prior or active chemotherapy or radiation therapy (solid malignancy), solid organ transplant, autoimmune disease, and primary immunodeficiency. Patients without immunosuppressive diseases or history of ISMT use were included in the NISP (non-immunosuppressed patient) cohort. All other patients were included in the ISP (immunosuppressed patient) cohort. Patients with a documented history of SARS-CoV-2 infection or without vaccination, disease, or therapy documentation in the EMR were excluded from the analysis.

Immunocompetent healthcare worker (HCW) volunteers without known history of SARS-CoV-2 infection served as a reference cohort. Anti-S1 IgG and IGRA were collected between 14 and 25 days and then at approximately 5-and 9-months following primary vaccination with BNT162b2. Anti-S1 IgG and IGRA were collected between 8-and 34-days following receipt of a booster dose of the BNT162b2 vaccine in a subset of these HCWs.

Statistical analyses and graphing were performed in Python version 3.8.5 using the packages pandas, matplotlib, seaborn, numpy, scipy, and statsmodels. Linear regression was performed by method of ordinary least squares. Unless otherwise indicated, Fisher exact test was used for all statistical comparisons, and α =.05. See eMethods for detailed descriptions.

We focused the analysis on anti-S1 IgG and IGRA positivity rates, rather than quantitative values, which decline over time (eFigure 1) 9, 14 . The HCW cohort anti-S1 IgG values were used to establish a reference range for expected (i.e. immunocompetent) anti-S1 IgG levels over time after primary vaccination. A cutoff was established based on this reference range for "high" IgG, indicating expected IgG levels over time, All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted January 5, 2022. ; 8 and "low" IgG (eMethods). The same cutoff was not established for IGRA results due to the stochasticity observed with this assay. All rights reserved. No reuse allowed without permission.

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A total of 496 patients were included in this study. Cohort sample size and assay result availability are presented in eTable 5.

Demographic information and assay results from 18 HCWs, 28 NISPs, and 427 ISPs following primary vaccination are displayed in Table 1 (see also eTables 6,7). The difference in anti-S1 IgG (62%) and IGRA (71%) positivity rates in ISPs was statistically significant (P=.009). In 381 ISPs that had both anti-S1

IgG and IGRA results available, 51% were positive for both (196), 18% were negative for both (67), 20%

were IGRA positive only (75), and 11% were IgG positive only (43).

For ISPs with only a single disease category, the anti-S1 IgG and IGRA positivity rates were generally lower for those on ISMT than those not on ISMT, albeit this was only statistically significant for patients with inactive hematological malignancy ( Figure 1 ). Overall, ACE2 blocking results showed similar positivity rates as anti-S1 IgG ( Figure 1 , eFigure 2).

For patients not on ISMTs, two categories had high rates of humoral and cellular response, comparable to those of NISPs: primary anemia and solid malignancy. Primary anemia patients not on ISMT were 88% IgG positive (7/8), 88% IgG high (7/8), and 100% IGRA positive (8/8). Solid malignancy patients were 92% IgG positive (12/13), 85% IgG high (11/13), and 91% IGRA positive (10/11). Notably, solid malignancy patients on ISMT also had relatively high response rates compared to NISPs, at 82% IgG positive (9/11, P=.08), 73% IgG high (8/11, P=.13) , and 73% IGRA positive (8/11, P=.14).

Two categories of patients not on ISMTs had low rates of humoral response compared to NISPs but high rates of cellular response: autoimmune disease and inactive hematologic malignancy. Autoimmune disease patients not on ISMT were 69% IgG positive (11/16, P=.005), 56% IgG high (9/16, P=.008), and All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted January 5, 2022. Primary immunodeficiency and active hematologic malignancy patients not on ISMT had low rates of both humoral and cellular response; however the rates of cellular response were not significantly lower than that of NISPs. Primary immunodeficiency patients were 80% IgG positive (32/40, P=.02), 53% IgG high (21/40, P<.001), and 75% IGRA positive (30/40, P=.11). Active hematologic malignancy patients were 58% IgG positive (7/12, P=.001), 17% IgG high (2/12, P<.001), and 64% IGRA positive (7/11, P=.05).

Results of a systematic screen of immunosuppressive factors associated with low and high rates of P<.009) were associated with a low rate of cellular response specifically. Conversely, liver transplant (n=15, P<.001) and solid malignancy (n=34, P=.001) were associated with a high rate of humoral response, while anti-CD20 mAbs, specifically ocrelizumab (n=24, P=,008) were associated with a high rate of cellular response.

Results of multivariable linear regression to identify individual effects of immunosuppressive factors and certain demographic factors on humoral and cellular response are presented in eTable 12,13. All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted January 5, 2022. Analysis of 41 patients with immunoglobulin deficiency, without other immunosuppressive diseases and not on any ISMT, was underpowered to definitively identify a difference in vaccine response due to All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted January 5, 2022. ; immunoglobulin therapy. However, while female patients on immunoglobulin therapy were 100% IgG positive (11/11), 64% IgG high (7/11), and 91% IGRA positive (10/11), male patients had much lower rates especially with humoral response, at 27% IgG positive (3/11, P=.001), 9% IgG high (1/11, P=.02), and 58% IGRA positive (7/12, P=.15) ( Figure 2C, eFigure 7) . Patients who received HSCT within one year prior to vaccination, without active hematologic malignancy, were 92% IgG positive (12/13), 69% IgG high (9/13), 73% IGRA positive (8/11) ( Figure 2E ). These response rates were comparable to those who received HSCT greater than one year prior to vaccination, which were 84% IgG positive (27/32), 81% IgG high (26/32), and 83% IGRA positive (25/30). All rights reserved. No reuse allowed without permission.

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Patients with multiple anti-S1 IgG and IGRA results after primary vaccination showed that the average rates of decline for both humoral and cellular response in ISPs were comparable to those of HCWs and NISPs ( Figure 3A, eFigure 9) . The average rate of change of log transformed anti-S1 IgG OD ratio is - Notably, the standard deviation in the rate of humoral response change over time was 4-fold higher in ISPs than in HCWs and NISPs combined. For cellular response, the standard deviation of the rate of change is much more comparable between ISPs and HCWs plus NISPs, with a 0.8-fold difference.

Importantly, the rate of change in vaccine response over time did not correlate with the initial anti-S1 IgG Figure 3B ). For anti-S1 IgG, the relationship between rate of change and initial value displays heteroscedasticity, where the variance in the rate of change was higher towards the low end of the initial value. After investigation, we attributed this heteroscedasticity mainly to the imprecision of the anti-S1 IgG assay, which particularly at low values, become magnified by log transformation (eResults).

Demographic information and assay results from 6 immunocompetent HCWs, 6 NISPs, and 125 ISPs after booster vaccination are displayed in Table 2 (see also eTables 14,15). The difference in anti-S1 IgG (69%) and IGRA (73%) positivity rates in ISPs was not statistically significant (P=.48). In 117 ISPs that had both anti-S1 IgG and IGRA results available, 55% were positive for both (64), 14% were negative for both (16) , 18% were IGRA positive only (21) , and 14% were IgG positive only (16) .

In the paired booster cohort of 6 HCWs, 1 NISP, and 84 ISPs with anti-S1 IgG or IGRA results collected before and after the booster dose, testing occurred a median of 89 days after primary vaccination, and 36 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted January 5, 2022. ; https://doi.org/10.1101/2022.01.04.22268750 doi: medRxiv preprint days after booster. To correct for this collection time difference, we applied the average rate of vaccine response decline over time after the primary dose ( Figure 3C ) to predict the expected non-anamnestic booster responses (where the response after primary and booster doses are the same). This allowed us to determine, with statistical confidence, patients who had anamnestic booster responses ( Figure 3D , eFigure 10, eMethods, eResults). Of 40 ISPs with both paired anti-S1 IgG and paired IGRA results available, 10 had an anamnestic humoral booster response and two had an anamnestic cellular booster response, a statistically significant difference (P=.03). Notably, 35% (18/52) ISPs with low humoral response after primary vaccination had an anamnestic booster response ( Figure 3E ). We focused the rest of the analysis on humoral booster response, and specifically on patients with low humoral response after the primary doses.

Patient age and duration between primary vaccination and booster doses were not associated with booster response ( Figure 3F ). Patients with immune defects due to disease and not necessarily ISMT (hematologic malignancy and primary immunodeficiency patients) had low rates of anamnestic response of 16% (4/25), while patients with immunodeficiency due to ISMT use (solid malignancy, solid organ transplant, and autoimmune disease patients) had higher rates of anamnestic response of 52% (14/27, P=.009) ( Figure 3G ).

Following boosters, 50% of patients on anti-CD20 mAbs had an anamnestic response (4/8), 0% for S1P receptor modulators (0/2), 56% for mycophenolate (5/9), and 50% for systemic steroids (5/10). 20% of patients with acute leukemia had an anamnestic response (1/5), 18% for B cell lymphoma (2/11), 33% for plasma cell disease (1/3), and 0% for CVID (0/4) (eFigure 11).

Eight patients had their ISMT dosage temporarily decreased by their provider to try to elicit an anamnestic booster response. Three of these patients had an anamnestic response (38%), a rate comparable to patients who did not have their ISMT altered (43%, 12/28) ( Figure 3H , eResults). All rights reserved. No reuse allowed without permission.

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We identified patient factors affecting immune response to primary and booster SARS-CoV-2 vaccines in a large heterogeneous cohort of immunosuppressed patients. We found more immunosuppressive factors associated with low humoral response than low cellular response, corresponding with the lower rate of anti-S1 IgG positivity (62%) compared to IGRA (71%) in immunosuppressed patients. In concordance with other studies [15] [16] [17] [18] [19] [20] [21] [22] [23] , we found that anti-CD20 mAb and S1P receptor modulator use are associated with decreased humoral response. Unlike anti-CD20 mAb use, S1P receptor modulator use is also associated with low rates of cellular response. We showed that antimetabolite/mycophenolate use is the strongest predictor of decreased humoral and cellular response in transplant recipients, in concordance with other studies 4 . In autoimmune patients, however, mycophenolate monotherapy was not definitively associated with decreased humoral or cellular response. While monotherapy with either a calcineurin/mTOR inhibitor or mycophenolate was not associated with decreased vaccine response, combination therapy was. HSCT patients without active hematologic malignancy had relatively high rates of humoral and cellular response, even if vaccinated less than one year from transplantation. This is concordant with findings from one study 24 , but not another 25 . Notably, results from the latter study may be confounded by recurrent/residual disease after HSCT.

Hematological malignancies were associated with lower vaccine response than solid malignancies, consistent with other reports 15, 16, 20, 22, 26, 27 . Interestingly, patients with a history of B cell lymphomas or plasma cell diseases, not on ISMT, had low rates of humoral response but high rates of cellular response, while those with a history of acute leukemias, such as B lymphoblastic leukemia, had high rates of both humoral and cellular response. Primary hypogammaglobulinemia disorders were associated with decreased humoral response, particularly in male patients. It has been shown that men typically produce lower antibody responses to non-SARS-CoV-2 vaccines 28 , an effect likely amplified in hypogammaglobulinemia.

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The copyright holder for this preprint this version posted January 5, 2022. ; Importantly, we did not find evidence that the rate of decline in humoral and cellular response over time differ between non-immunosuppressed individuals and ISPs. This allowed us to predict the expected nonanamnestic and anamnestic booster responses for each patient.

We find no strong evidence that boosters improve cellular response in ISPs, in concordance with a previous report in cancer patients 29 , but contradicting other studies 23, 30 . The rate of anamnestic humoral response after booster in patients with poor humoral response after primary vaccination was 35%.

Interestingly, patients with poor response to primary vaccination due at least in part to the immunosuppressive effect of their primary disease were unlikely to have an anamnestic booster response. Meanwhile, patients with poor response to primary vaccination due to therapy were more likely to have an anamnestic booster response. This suggests that the immunosuppressive effects of ISMTs, such as anti-CD20 mAbs, can be overcome with booster immunization. Finally, although the analysis may be underpowered, we find no evidence that temporary ISMT dose reduction leads to a higher rate of anamnestic booster response.

Although this study was strengthened by evaluating vaccine responses in a large heterogeneous cohort of immunosuppressed patients, limitations include the small sample size of certain patient disease and ISMT categories, and a lack of information on drug dosages and history of prior therapy. Additionally, there were no pediatric patients included in NISP cohort.

As the COVID-19 pandemic ensues and new SARS-CoV-2 variants arise, our findings provide an evidence-based framework for clinicians to determine optimal vaccination strategy in immunosuppressed patients. While numerous studies have examined humoral response to SARS-CoV-2 vaccination in particular immunosuppressed subgroups, relatively few have examined concurrent cellular response. This study shows that immunosuppressive conditions differentially impact humoral and cellular responses to SARS-CoV-2 vaccines, with 20% of patients only developing a cellular response following initial vaccination. The importance of cellular response in anti-SARS-CoV-2 immunity is supported by several reports 8,31-35 and a recent study showed that emerging SARS-CoV-2 variants that escape humoral All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted January 5, 2022. ;  immunity in vaccinees may not escape cellular immunity 36 . Humoral and cellular responses, therefore, provide complementary protection against SARS-CoV-2 in immunosuppressed patients. This emphasizes the importance of monitoring both humoral and cellular responses to vaccination, especially in immunosuppressed patients, and the utility of performing cellular immunity testing in the clinical laboratory.

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De-identified raw data used in the study is available upon request. Anti-S1 IgG, median (IQR), OD ratio 9.6 (9.3-9.9) 5.7 (3.6-8.2) *Number of days elapsed between primary vaccination and anti-S1 IgG testing. ^Number of days elapsed between primary vaccination and IGRA testing.

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The copyright holder for this preprint this version posted January 5, 2022. Anti-S1 IgG positive cutoff is set at ≥ 1.1 (OD ratio). High anti-S1 IgG is determined by the lower bound of the 95% confidence interval (CI) calculated using equation 1 (eMethods (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 5, 2022. (eMethods). Booster responses that fall above the upper bound of the 70% CI (pink region) are determined to be anamnestic. E) ISP (n = 52) cohort with low anti-S1 IgG after primary vaccination separated into nonanamnestic/decreased booster response (n = 34) and anamnestic booster response (n = 18), showing both the response after primary vaccination (orange dots) and after booster (blue dots). F) Distribution of age and days between primary vaccination and booster in non-anamnestic and anamnestic booster response patients. G) Anamnestic booster response rates in patients stratified by the likely primary cause of low humoral (anti-S1 IgG) response after primary vaccination (disease: heme malignancy and primary immunodeficiency patients, ISMT: solid malignancy, solid organ transplant, and autoimmune disease patients) All rights reserved. No reuse allowed without permission.

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Note: not all patients had both anti-S1 IgG and IGRA results available. *Number of days elapsed between primary vaccination and anti-S1 IgG testing. ^Number of days elapsed between primary vaccination and IGRA testing

We thank all study participants, providers and nursing staff caring for immunocompromised patients evaluated in this study. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Anti-S1 IgG, % positive (n) 100 (18/18)